Domino reactions for the synthesis of anthrapyran-2-ones and the total synthesis of the natural product (±)-BE-26554A

Article abstract of DOI:10.1021/ol402240v

A domino alkyne addition/CO insertion/Nu acylation reaction to a series of novel anthrapyran-2-ones in good to excellent yields is described. In addition, an efficient synthetic sequence involving carbonylation, formation of a β-keto-sulfoxide, and cyclization is presented en route to the antibiotic and antitumor compound (±)-BE-26554A.

Full text of DOI:10.1021/ol402240v

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Domino Reactions for the Synthesis of
Anthrapyran-2-ones and the Total Synthesis
of the Natural Product (()-BE-26554A
James E. Rixson,† Brian W. Skelton,‡ George A. Koutsantonis,† Kersten M. Gericke,§
and Scott G. Stewart*,†
The School of Chemistry and Biochemistry, and Centre for Microscopy,
Characterisation and Analysis, The University of Western Australia, Crawley, WA 6009,
Australia, and Bayer Pharma AG, Medicinal Chemistry, 42096 Wuppertal, Germany
scott.stewart@uwa.edu.au
Received August 7, 2013
ABSTRACT
A domino alkyne addition/CO insertion/Nu acylation reaction to a series of novel anthrapyran-2-ones in good to excellent yields is described. In
addition, an efficient synthetic sequence involving carbonylation, formation of a β-keto-sulfoxide, and cyclization is presented en route to the
antibiotic and antitumor compound (()-BE-26554A.
Domino reactions have providedmore efficient methods
for the synthesis of a range of complex ring systems in
industry and academia.1 The discovery and optimization
of domino reactions also provides efficient access to a
variety of new compounds, sometimes having interesting
pharmacological properties.2,3 In this regard, the structur-
al class of anthrapyranones have a remarkable range of
biological activity mainly as antibacterial agents or anti-
tumor compounds. Some examples in this family of com-
pounds are pluramycin A, kidamycin, and the antibiotic
saptomycin E.4,5 In 1994, the related compound BE-
26554A (1)6 has been isolated from Streptomyces A26554
cultures by the Banyu Pharma group. This anthrapyran-4-
one and the C2-functionalized analogues have an excellent
range of IC50 values of 0.017ꢀ0.0007 μM in P388 leukemia
cells. Given this evaluation of 1 and its derivatives, these
compounds provide excellent synthetic targets to enable
further biological evaluation.
The synthesis of natural product anthrapyranones has
seen several different approaches from various groups.7
Originally, we conceived the application of a domino CO
insertion/Sonogashira/6-exo-dig cyclization of aryl halides
as a possible alternative, offering a rapid approach to the
construction of the D-ring found in such natural products.
This approach has been used for the production of various
heterocycles8 including chromones as well as flavones
† The School of Chemistry and Biochemistry, The University of Western
Australia.
‡ Centre for Microscopy, Characterisation and Analysis, The University of
Western Australia.
§ Bayer Pharma AG.
(1) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(2) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442.
(3) Hayato, I.; Takaki, S.; Yujiro, H. Angew. Chem., Int. Ed. 2009, 48,
1304.
(4) Abe, N.; Enoki, N.; Nakakita, Y.; Uchida, H.; Nakamura, T.;
Munekata, M. J. Antibiot. 1993, 46, 1536.
(5) Abe, N.; Nakakita, Y.; Nakamura, T.; Enoki, N.; Uchida, H.;
Munekata, M. J. Antibiot. 1993, 46, 1530.
(6) Ojiri, K.; Saito, K.; Nakajima, S.; Suda, H. Jpn. Kokai Tokkyo
Koho 1994, JP 06228121 A 19940816.
(7) (a) Tietze, L. F.; Gericke, K. M; Singidi, R. R Angew. Chem., Int.
Ed. 2006, 45, 6990. (b) O’Keefe, B. M.; Mans, D. M.; Kaelin, D. E.;
Martin, S. F. J. Am. Chem. Soc. 2010, 132, 15528. (c) Krohn, K.; Tran-
Thien, H. T.; Ahmed, I. Eur. J. Org. Chem. 2011, 12, 2223. (d) Fei, Z.;
McDonald, F. E. Org. Lett. 2007, 9, 3547. (e) Wright, B. J. D.; Hartung,
J.; Peng, F.; Van de Water, R.; Liu, H.; Tan, Q.-H.; Chou, T.-C.;
Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 16786. (f) Hsu, D.-S.;
Matsumoto, T.; Suzuki, K. Chem. Lett. 2006, 35, 1016. (g) Uno, H.;
Sakamoto, K.; Honda, E.; Ono, N. Chem. Commun. 1999, 11, 1005. (h)
Hauser, F. M.; Rhee, R. P. J. Am. Chem. Soc. 1979, 101, 1628.
r
10.1021/ol402240v
XXXX American Chemical Society

carbonylation process.12 In rare instances (and often with
lower yields/different regioselectivity), such reactions have
been demonstrated in the formation of simpler coumarins
with terminal alkynes.13,14 Reactions with internal alkynes
have been reported by Larock, suggesting a similar type of
mechanism.15 In order to optimize the conditions for the
production of 8 and 9 we carried out a series of reactions
under various catalytic conditions (Table 1).
Scheme 1. BE-26554A (1) and a Domino CO Insertion/
Sonogashira/6-Exo-Dig Cyclization to Chromones and Flavones
Table 1. Methodological Development of Domino Alkyne
Insertion/Carbonylation/Nu-Acylation Reaction
(Scheme 1, 2 to 3).9 For our purposes, previously estab-
lished carbonylative Sonogashira reaction conditions
could be used as a guide for more complicated substrates.9d
In this context, CO insertion into a Pdꢀaryl bond was
found tobechallenging in a stericallyhinderedortho,ortho-
disubstituted position.10 For the application of this dom-
ino reaction we required the halogenated anthraquinone 6,
where methodology, described earlier for the protonated
variant 5, was available (Scheme 2).11,7a Iodination of 5,
using iodic acid and iodine, furnished the domino precur-
sor aryl iodide 6 in excellent yield (84%).
temp (°C)/CO yield (%)
entry
catalytic conditions
Pd(PPh3)2Cl2
pressure (bar) (ratio 8:9)
1
2
3
4
5
6
7
8
9
60/20
60/60
60/20
60/20
60/1
82 (2.7:1)
Pd(PPh3)2Cl2
53 (2:1)
0a
Pd(PPh3)2Cl2, CuI
Pd(PPh3)2Cl2 (5:1 dioxane/H2O)
Pd(PPh3)2Cl2
Scheme 2. Domino CO Insertion Reaction Resulting in Isomers
8 and 9
0
67 (6.4:1)
0a
Pd2(dba)3 CHCl3, Xantphos
60/20
60/20
60/20
60/20
60/20
60/20
60/20
3
Pd2(dba)3 CHCl3, t-Bu3P
30
3
Pd2(dba)3 CHCl3, XPhos
43b
3
Pd(OAc)2, Ad2Pn-Bu
0a
10 PEPPSI-iPr
28 (2.5:1)b
NR
11 Pd(dppf)Cl2
12 [(cinnamyl)PdCl]2
NR
a Reaction resulted in complex mixture of products. b In each of these
cases a large amount of product resulting from protonation of 6 resulted.
Modifications of the Pd(PPh)3Cl2-catalyzed reaction,
such as changing the solvent system and using a copper
additive, were less effective. Interestingly, increasing the
pressure of CO (entry 2) still resulted in production of the
2-pyranone derivatives, but in a lower yield, while a
decrease of pressure dramatically improved the regioselec-
tivity (ca. 6:1 for 8:9, entry 5). We propose that an alkyne
Pdprecomplexation equilibriumprocessatlowerpressures
is a dominant factor in this result. In order to produce
intermediates with more electron density on the palladium,
the electron-rich phosphine systems (entries 6ꢀ9) were
tested. However, these were also less efficient; the back-
donation to the carbonyl ligand possibly slowed down the
initial CO insertion step.16 Pd(dppf), [(cinnamyl)PdCl]2,
and the bis-adamantyl n-butyl phosphine (cataCXium,17,18
all failed to deliver any pyranone ring containing products.
Unlike the previously discussed work preparing the
simpler chromones,9 but similar to the early carbonylative
cross coupling work in the anthraquinone series of the
Martin group,7b under standard conditions we were also
unable to produce the anthrapyran-4-one ring system 7.
However, when 1-octyne and aryl iodide 6 were reacted
the anthrapyran-2-one ring regioisomers 8 and 9 were
isolated in excellent yields (82%), signifying a late-stage
(8) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Rev. 2012, 113, 1.
(9) (a) Yang, Q.; Alper, H. J. Org. Chem. 2010, 75, 948. (b) Liang, B.;
Huang, M.; You, Z.; Xiong, Z.; Lu, K.; Fathi, R.; Chen, J.; Yang, Z.
J. Org. Chem. 2005, 70, 6097. (c) Awuah, E.; Capretta, A. Org. Lett.
2009, 11, 3210. (d) Kalinin, V. N.; Shostakovsky, M. V.; Ponomaryov,
A. B. Tet. Lett. 1990, 31, 4073. (e) Torii, S.; Okumoto, H.; Xu, L. H.;
Sadakane, M.; Shostakovsky, M. V.; Ponomaryov, A. B.; Kalinin, V. N.
Tetrahedron 1993, 49, 6773. (f) Ma, W.; Li, X.; Yang, J.; Liu, Z.; Chen,
B.; Pan, X. Synthesis 2006, 2489.
(12) Single X-ray crystal structures of 1, 8, 10J, 10K, 12, 13, and the
des-methyl compound can be found in the Supporting Information
(13) Kadnikov, D. V.; Larock, R. C. J. Organomet. Chem. 2003, 687,
425.
(10) Barnard, C. F. J. Organometallics 2008, 27, 5402.
(11) Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455.
(14) Cao, H.; Xiao, W.-J. Can. J. Chem. 2005, 83, 826.
(15) Kadnikov, D. V.; Larock, R. C. Org. Lett. 2000, 2, 3643.
B
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Previous reports of reactivity in carbonylative reactions
involving ortho,ortho-disubstituted aryl halides prompt-
ed the choice of the PEPPSI-iPr ligand (entry 10);10,19
however, none of the pyran-4-one ring system was
observed.20 Interestingly, the main byproduct of this
reaction, especially when using palladium(0) catalysts,
was the dehalogenated compound (see the Supporting
Information). Once the optimum conditions for the dom-
ino process were established we investigated a series of
alkynes to provide insight into the tolerance and scope of
this reaction (Table 2). Alkynes containing alkyl groups
perform well in the domino process with consistently high
yields (entries 1ꢀ3). However, the reaction of phenylace-
tylene was less productive (20%). A range of protected
and unprotected alcohols also performed very well in this
transformation. High yields resulted in the synthesis of
the alkyl chloride 10i and the vinyl silane 10j, allowing
for two excellent functionalities for further synthetic
transformations. Interestingly, the complex alkyne, bear-
ing an olefin, underwent an additional [2 þ 2] visible light
promoted cycloaddition following workup to produce the
heptacycle 10k. Nitriles and some protected amines were
not as high yielding under the general conditions proposed
previously and may require additional optimization.
In order to investigate the reasons why no pyran-4-one
ring system was formed, we examined a stepwise reaction
process. Here we attempted the isolation of the Pd(II)
putative catalytic precursor and its subsequent reaction
with CO (Scheme 3), reasoning that the early CO insertion
was a key step. Treatment of anthraquinone iodide 6 with
1 equiv of Pd(PPh3)4 in benzene provided isolable crystals
of the iodinated oxidative addition product 12 (Figure 1).
Treating this iodide (12) or the chloride (13) under car-
bonlyative conditions (CO, 20 bar) resulted in recovery
of only the organometallic starting materials with no
evidence of acyl complex formation.16 The electronegativ-
ity of the halide appears to play no role in the reactivity of
the proposed oxidative addition species to carbonylation
or the occurrence of a reversible CO insertion exits. The
des-methyl variant of 12 was also prepared to examine the
hypothesis that carbonylation was affected by the sterics of
the ortho,ortho-disubstitution;10 however, carbonylation
was again ineffective, suggesting that the electronics of
the anthraquinone system play a large role in this proposed
domino process. We provide a more expansive discussion
of the possible mechanism in the Supporting Information.
As an alternative pathway to the synthesis of the pyran-
4-one ring system of 1 we were attracted to a new method
for pyran-4-one formation through β-keto-sulfoxides as
annulation precursors (Scheme 4).21
Table 2. Methodological Evaluation of Various Alkynes
Domino Alkyne Insertion/Carbonylation/Nu-Acylation Reaction
(16) (a) Garrou, P. E.; Heck, R. F. J. Am. Chem. Soc. 1976, 98, 4115.
(b) Korsager, S.; Taaning, R. H.; Skrydstrup, T. J. Am. Chem. Soc. 2013,
135, 2891–2894. (c) Ben-David, Y.; Portnoy, M.; Milstein, D. J. Am.
Chem. Soc. 1989, 111, 8742–8744.
€
(17) Neumann, H.; Brennfuhrer, A.; Beller, M. Chem.;Eur. J. 2008,
14, 3645.
ꢀ
(18) Schareina, T.; Zapf, A.; Cotte, A.; Gotta, M.; Beller, M. Adv.
Synth. Catal. 2010, 352, 1205.
(19) O’Keefe, B. M.; Mans, D. M.; Kaelin, D. E., Jr.; Martin, S. F.
a Reaction run under a balloon of CO. b In this example, a significant
amount of Sonogoshira product was observed. c An additional [2 þ 2]
reaction was observed to afford 10k; see the Supporting Information.
Tetrahedron 2011, 67, 6524.
(20) O’Keefe, B. M.;Simmons, N.;Martin, S. F.Org. Lett. 2008, 10, 5301.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Attempted CO Insertion of Pd Complexes 12 and 13
Scheme 4. Synthesis of (()-BE-26554A (1)
Figure 1. X-ray structures of 12 and (()-BE-26554A (1).
Treatment of the phenol 6 with carbon monoxide, base,
and methanol resulted in the formation of the methyl ester
in variable yields. Given that alkoxycarbonylation of
phenols has been reported,22 we accordingly benzyl pro-
tected this functionality. Alkoxycarbonylation of deriva-
tive 15 resulted in efficient conversion to the ester 16 in
reproducible yields (ca. 82%). Both protection of the
B-ring within compound 16 to the dimethoxyanthracene
derivative 17 and subsequent benzyl deprotection pro-
ceeded in high yields. The resulting hydrogenolysis prod-
uct, ester 18, was treated with lithium methylsulfinyl-
methide to furnish the β-ketosulfoxide 19 in an excellent
yield.21c Formation of the pyran-4-one ring system was
achieved through reaction of 19 with propionaldehyde and
catalytic amounts of piperidine. Oxidative demethylation
established the anthraquinone core revealing compound
21. Following the Augustine olefination procedure,23
treating the pyranone 21 with a bis(pyridinium) cation
species generated from BrClCH2 and pyridine in DMF
gave the desired alkene (isolated crude) in 57% yield.7c
Smooth cleavage of the isopropyl group from the A-ring,
revealing phenol 22, was achieved by treatment with BCl3.
Final epoxidation with m-CPBA allowed for the synthesis
of the natural product (1). The 1H and 13C spectral data for
compound 3 matched those in the early report published
by the Banyu Pharma group.
In summary, we have demonstrated a straightforward
approach to a new series of anthrapyran-2-ones. Further-
more, the first total synthesis of the bioactive natural
product (()-BE-26554A (1) was developed utilizing an
efficient β-keto-sulfoxideꢀannulation procedure for the
construction of the pyran-4-one moiety. We intend to use
this methodology for the synthesis of the other series of
BE-compounds reported and carry out further investiga-
tions into their biological activity.
Acknowledgment. We thank A. Professor Lindsay Byrne
for NMR assistance. We are indebted to Xiangyang Ni
(Frank) for assistance in the laboratory and to Dr Tony
Reader for mass spectrometry support. Access to the facilities
at the Centre for Microscopy, Characterisation and Analysis,
University of Western Australia, is kindly acknowledged.
(21) (a) Kozlowski, M. C.;Dugan, E. C.;DiVirgilio, E. S.;Maksimenka,
K.; Bringmann, G. Adv. Synth. Catal. 2007, 349, 583. (b) Gramatica, P.;
Gianotti, M. P.; Speranza, G.; Manitto, P. Heterocycles 1986, 24, 743. (c)
Von Strandtmann, M.; Klutchko, S.; Cohen, M. P.; Shavel, J. J. Heterocycl.
Chem. 1972, 9, 171.
Supporting Information Available. Experimental data,
1H and 13C NMR spectra for all the new compounds, and
CIF file. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Wu, X.-F.; Neumann, H.; Beller, M. Chem.;Eur. J. 2012, 18,
3831.
(23) Augustine, J. K.; Naik, Y. A.; Mandal, A. B.; Chowdappa, N.;
Praveen, V. B. J. Org. Chem. 2007, 72, 9854.
The authors declare no competing financial interest.
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